Tumors have the ability to spread to many different parts of the body but will preferentially colonize a specific set of organs and tissues (Paget S (1989) Cancer Metastasis Rev 8(2):98-101), an observation that has many clinical examples (Chiang A C & Massague J (2008) N Engl J Med 359(26):2814-2823; Nguyen D X, et al. (2009) Nat Rev Cancer 9(4):274-284). For instance, 50% of patients with uveal melanoma develop liver metastases 10-15 years after initial diagnosis (Bakalian S, et al. (2008) Clin Cancer Res 14(4):951-956; Sato T (2010) Semin Oncol 37(2):127-138). Breast cancer has the propensity to metastasize to the bone, lungs, liver and brain (Chiang A C & Massague J (2008) N Engl J Med 359(26):2814-2823; Nguyen D X, et al. (2009) Nat Rev Cancer 9(4):274-284), prostate cancer metastases almost exclusively to the bone (Scharffetter-Kochanek K, et al. (1998) J Exp Med 188(1):119-131), colorectal and pancreatic cancer tend to metastasize to the liver (Hess K R, et al. (2006) Cancer 106(7):1624-1633; Jones S, et al. (2008) Proc Natl Acad Sci USA 105(11):4283-4288) while soft tissue sarcoma spreads predominantly to the lung (Roberge D et al. (2010) Curr Oncol 17(6):18-22). Taken together, these studies highlight a real need for loco-regional management of specific cancers, a need that requires consideration of the tumor cells and the host microenvironment within a specific organ. These observations reinforce the original hypothesis from Dr. Paget that certain tumors (the “seeds”) have specific affinity for particular organs (“soil”) and the compatibility between the “seed” and “soil” determines the final fate of the tumor cells at that site. This premise can be expanded to incorporate the idea that the final destination of the “seed” requires the infiltrating cells of the adaptive and innate immune system to determine whether tumor cell colonization of specific organ sites will succeed or fail.
There are distinct sequential stages of the metastatic process: 1) tumor cells escape the primary tumor mass and enter the circulation either by the lymphatic system or the blood vasculature, 2) survival of the cancer cell within the circulation, 3) initial arrest within the vasculature, 4) extravasation, 5) establishment of a micrometastasis that involves the contribution of host cells within the microenvironment and 6) further growth into macrometastases, which requires adaptation of the foreign tissue microenvironment.
Using a combination of in vivo selection, genetic and pharmacological approaches, variants of breast, pancreatic and colorectal cancer have been identified that have a high propensity to metastasize to the liver ((Du Y C, et al. (2011) Proc Natl Acad Sci USA 108(40):16753-16758; Bemmo A, et al. (2010) PLoS One 5(8):e11981; Tabaries S, et al. (2011) Oncogene 30(11):1318-1328; Tabaries S, et al. (2012) Mol Cell Biol.; Kang Y, et al. (2003) Cancer Cell 3(6):537-549). These variants demonstrate unique gene expression signatures and more specific target organ selectivity than the parental tumor cells (Minn A J, et al. (2005) Nature 436(7050):518-524; Bos P D, et al. (2009) Nature 459(7249):1005-1009; Landemaine T, et al. (2008) Cancer Res 68(15):6092-6099; Minn A J, et al. (2005) J Clin Invest 115(1):44-55; Zhang X H, et al. (2009) Cancer Cell 16(1):67-78; Massague J (2007) N Engl J Med 356(3):294-297). These organ specific features coupled with the observation that each organ's vasculature has unique cell surface addresses or ‘zip codes’ (Ruoslahti E (2004) Biochem Soc Trans 32(Pt3):397-402; Teesalu T, et al. (2012) Methods Enzymol 503:35-56) raise the intriguing possibility that cancer cells can ‘match’ to their metastatic environment based on specific recruitment mechanisms.
What is therefore needed are compositions capable of blocking the attachment of tumor cells in the blood to the vascular supplying metastatic target organs, such as liver and lungs, to prevent or inhibit tumor metastasis to these organs. What is also needed are compositions effective to treat other diseases associated with leukocyte recruitment including sepsis such as bacterial sepsis.